The pathoetiology of multiple sclerosis (MS) involves underlying genetic susceptibility acting in concert with undefined environmental factors. African Americans (AAs) with MS are a unique population that may allow a better understanding of the biology of MS. AA patients have an older age of onset, are at high risk for optic nerve and spinal cord manifestations and suffer from a more severe disease course. Because these characteristics are more prevalent in AAs than in White Americans (WAs), identification of the underlying genes associated with these traits will be more readily accomplished in AAs. Furthermore compared to WA chromosomes, AA chromosomes have smaller blocks of linkage disequilibrium allowing higher resolution genetic mapping in this population. The goals of this proposal are two fold. The first goal is to develop robust and well-characterized cohorts of AA and WA MS patients. To date, 534 AAs and 672 WAs have been recruited and we will recruit a total of 1,000 affected subjects in each group within the first 2 years of this project. The second goal is to use this dataset to identify specific disease alleles that modify disease expression. This dataset has already attained sufficient statistical power to detect phenotypic differences between these populations and, when complete, should have adequate power to make phenotype-genotype correlations. There are currently three loci that have the most consistent association with MS: 6p21, 19q13, and 17q22. Although the HLA-DRB, APOE, and iNOS genes are assumed to account for the effect of these respective loci, the confounding consequences of linkage disequilibrium in WAs prevent definitive mapping of the MS genes. In parallel with this proposal, fine mapping studies will be performed using the AA cohort to determine the genes at these loci associated with MS susceptibility and disease expression. Specific alleles will then be tested for association with MS phenotypes. These studies are expected to substantially improve the understanding of the genetic basis of MS pathogenesis and have practical applications for prognosis and perhaps for therapeutic selection based on an individual's genetic background.